Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure

Ceccherini‐Silberstein, Francesca; Erba, Fulvio; Gago, Federico; Bertoli, Ada; Forbici, Federica; Bellocchi, Maria Concetta; Gori, Caterina; D’Arrigo, Roberta; Marcon, Luisa; Balotta, Claudia; Antinori, Andrea; Monforte, Antonella d’Arminio; Perno, Carlo Federico

doi:10.1097/01.aids.0000131394.76221.02

Cited by 55 publications

(66 citation statements)

References 47 publications

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“…Pol-amplified products (containing the entire protease and the first 335 amino acids of the RT open reading frame, 1302 nucleotides) were full-length sequenced in sense and antisense orientations by an automated sequencer (ABI 3130) by using seven different overlapping sequence-specific primers. 35 The sequences were analyzed using SeqScape-v.2.5 software. The quality endpoint for each individual was ensured by a coverage of the protease and RT sequence by at least two sequence segments.…”

Section: Rna Extraction Amplification Sequencing and Genetic Subtymentioning

confidence: 99%

Molecular Epidemiology of HIV Type 1 CRF02_AG in Cameroon and African Patients Living in Italy

Véras

Santoro

Gray

et al. 2011

AIDS Research and Human Retroviruses

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HIV-1 CRF02_AG accounts for > 50% of infected individuals in Cameroon. CRF02_AG prevalence has been increasing both in Africa and Europe, particularly in Italy because of migrations from the sub-Saharan region. This study investigated the molecular epidemiology of CRF02_AG in Cameroon by employing Bayesian phylodynamics and analyzed the relationship between HIV-1 CRF02_AG isolates circulating in Italy and those prevalent in Africa to understand the link between the two epidemics. Among 291 Cameroonian reverse transcriptase sequences analyzed, about 70% clustered within three distinct clades, two of which shared a most recent common ancestor, all related to sequences from Western Africa. The major Cameroonian clades emerged during the mid-1970s and slowly spread during the next 30 years. Little or no geographic structure was detected within these clades. One of the major driving forces of the epidemic was likely the high accessibility between locations in Southern Cameroon contributing to the mobility of the population. The remaining Cameroonian sequences and the new strains isolated from Italian patients were interspersed mainly within West and Central African sequences in the tree, indicating a continuous exchange of CRF02_AG viral strains between Cameroon and other African countries, as well as multiple independent introductions in the Italian population. The evaluation of the spread of CRF02_AG may provide significant insight about the future dynamics of the Italian and European epidemic.

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Section: Rna Extraction Amplification Sequencing and Genetic Subtymentioning

confidence: 99%

Molecular Epidemiology of HIV Type 1 CRF02_AG in Cameroon and African Patients Living in Italy

Véras

Santoro

Gray

et al. 2011

AIDS Research and Human Retroviruses

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“…20,21 Briefly, RNA was extracted, retrotranscribed by murine leukemia virus reverse transcriptase, and amplified with AmpliTaq Gold polymerase enzyme, using two different sequence-specific primers for 40 cycles. The full lengths of polymerase-amplified products (containing the entire protease and the first 335 amino acids of the reverse transcriptase open reading frame product) were sequenced in sense and antisense orientations by using seven different overlapping sequence-specific primers for the automated sequencer (ABI 3100).…”

Section: Specimen Collection and Dna Extractionmentioning

confidence: 99%

Non-B HIV Type 1 Subtypes among Men Who Have Sex with Men in Rome, Italy

Giuliani

Montieri

Palamara

et al. 2009

AIDS Research and Human Retroviruses

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An increase in the circulation of HIV-1 non-B subtypes has been observed in recent years in Western European countries. Due to the lack of data on the circulation of HIV-1 non-B subtypes among European HIV-1-infected men who have sex with men (MSM), a biomolecular study was conducted in Rome, Italy. HIV-1 partial pol gene sequences from 111 MSM individuals (76 drug naive and 35 drug experienced) were collected during the years [2004][2005][2006]. All these sequences were analyzed using the REGA HIV-1 Subtyping Tool, and aligned using CLUSTAL X followed by manual editing using the Bioedit software. A BLAST search for non-B subtype sequences was also performed. Twenty-six (23.4%) MSM were not Italians. Eight individuals (7.2%) were diag- The CRFs were more prevalent (8.1%) than pure subtypes (5.4%), which were distributed as follows: subtype C (2.6%), subtype A1 (1.7%), and subtype F1 (0.9%). Major mutations conferring resistance to antiretroviral drugs (ARV) were not found among HIV-1 non-B subtype drugnaive patients but were found in two ARV-experienced individuals. The data show that viral diversity is likely increasing in a population group that had been previously characterized by the circulation of HIV-1 subtype B.

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“…In general, substitutions in critical residues near the highly conserved active site of an enzyme [e.g., the protease catalytic site or the nucleo(s/t)ide incorporation site], are likely to impair enzyme function, resulting in diminished replicative capacity and decreased viral fitness. In contrast, substitutions at less critical residues which participate in the binding of the DAA have the potential to be better tolerated and result in enzymes and viral variants with a relatively lower fitness consequence (e.g., substitution at an allosteric site) (11).…”

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Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Bartels

Sullivan

Zhang

et al. 2013

J Virol

136

135

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The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3-to 25-fold increased 50% inhibitor concentration [IC 50 ]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC 50 ) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide activesite NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

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Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure

Cited by 55 publications

References 47 publications

Molecular Epidemiology of HIV Type 1 CRF02_AG in Cameroon and African Patients Living in Italy

Molecular Epidemiology of HIV Type 1 CRF02_AG in Cameroon and African Patients Living in Italy

Non-B HIV Type 1 Subtypes among Men Who Have Sex with Men in Rome, Italy

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

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